Rituximab is a humanized monoclonal antibody (Ab) against CD20 on B cells that is FDA-approved for the therapy of non- Hodgkin's lymphoma. It depletes B cells and plasmablasts (early plasma cells that still express CD20) from the circulation. Our preliminary data in three patients indicates B cells and plasmablasts are depleted from the CSF by rituximab. This K24 mid-career application is based upon a Phase II trial of rituximab in relapsing MS. Rituximab will be given at the standard dose of 4 intravenous doses of 375mg/m2. This regimen eliminates circulating cells expressing CD20 (B cells, plasmablasts) completely for 6-12 months. Circumstantial evidence strongly suggests that B cells and/or Ab are involved in the pathogenesis of MS. However, all data thus far are associative. To determine whether B cells truly play a role will require a controlled trial of their elimination to determine if the course of MS will be altered. We are undertaking a Phase II trial of the safety and MRI efficacy of Rituxan in 30 patients with active, relapsing MS, despite taking beta-interferon (BIFN) or glatiramer acetate (GA). All patients entering are volunteers and are fully informed of the risks involved and the alternatives. Patients continue taking BIFN or GA. To receive study drug, subjects must have at least one gadolinium-enhancing lesion on any of three pre-treatment brain MRIs, and must have had at least one clinical relapse in the 18 months prior to enrollment, despite being on a standard therapy (BIFN or GA). Endpoints are safety, in terms of toxicity and the possibility of worsening of MS, and efficacy based on MRI activity. The primary efficacy endpoint will be reduction in number of gadolinium-enhancing lesions on 3 brain MRIs performed post-treatment in comparison to the 3 MRIs performed pre-treatment. B cell and plasma cell numbers and activation status, level of immunoglobulin in the spinal fluid and serum will be measured pre- and post-treatment. Ab levels to several myelin antigens (human MOG, MBP, dilapidated and whole myelin) and MBP in CSF will be assayed pre- and post-treatment. The study takes place in the General Clinical Research Center at WUSM. Genentech is providing drug free-of-charge and some funding. The National MS Society has reviewed and approved this trial, and is funding the bulk of this trial, including MRI's, but the NMSS does not pay salaries of tenured faculty. PI spends 10 hrs per week seeing private outpatients, 2-6 hrs/week seeing inpatients, plus an additional 3-6 hrs/wk on dictations, disability forms, and dealing with phone calls related to private patients. PI also serves 2 mon/yr, on "service" as Neurology Ward or Consulting Attending and performs clinical trials Sponsored by pharmaceutical companies (reimbursement is better than for private patient care) in order to cover her salary. PI is applying for the K24 award to perform this trial, and to mentor junior persons as part of this and other research projects. With the K24, PI will decrease time devoted to private outpatients by 50%, will eliminate taking on any new private patients, and will transfer the care of many of her > 1,000 private patients to Drs. Parks and Naismith, and PI will be able to focus 30% more time on investigator-initiated trials and mentoring junior colleagues.